Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS). The safety and tolerability of PER has been well documented in 3 double-blind (DB), randomized, placebo (PBO)-controlled phase III trials. Here we present a post-hoc analysis of aggression-related safety from pooled PER phase III trials.Methods: Patients with refractory POS aged 12 yrs receiving 1-3 concomitant AEDs were enrolled in 3 phase III trials. Following 6-wk baseline, patients were randomized to once-daily, DB treatment (6-wk titration, 13-wk maintenance) with PBO or PER 8 or 12mg (trials 304 & 305); or PBO or PER 2, 4, or 8mg (trial 306). Trial results were pooled and included 1480 patients in the safety population. Treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) were reported using narrow and broad Standardized MedDRA Queries (SMQ) terms for hostility- and aggression-related events. Narrow and broad SMQs are groupings of MedDRA terms; a narrow SMQ identifies cases highly likely to represent the condition of interest and a broad SMQ identifies all possible cases, including broadly related cases. A subgroup analysis of adolescents (<16 yrs; N=84) vs adults ( 16 to <65 yrs; N=1368) for aggression-related events was also performed.Results: Safety population included 1038 patients in total PER and 442 in PBO. Aggression occurred in 17 (1.6%) of total PER vs 2 (0.5%) of PBO and anger in 12 (1.2%) of total PER vs 1 (0.2%) of PBO (Table 1). A dose relationship was observed using narrow SMQ terms for hostility/aggression, as shown by the increase in incidence rate over PBO for PER 8 & 12mg groups, driven mainly by aggression and anger. There were 4 SAEs in total PER groups (PER 2 mg: 1 SAE of aggression; PER 12 mg: 2 SAEs of aggression, 1 SAE of belligerence) vs 0 PBO. No patients experienced SAEs due to anger. TEAEs leading to discontinuation occurred in 1 patient in PER 8mg (aggression) and 9 patients in 12mg group (4 aggression, 4 anger, 1 belligerence) vs 0 PBO. None of the SAEs reported resulted in death. Using narrow and broad SMQ terms for hostility/aggression, there was an increase in incidence rate of TEAEs over PBO [25 (6%)] for PER 8mg [53 (12%)] and 12mg [52 (20%)], most commonly irritability [73 (7.0%) of total PER vs 13 (2.9%) of PBO] (Table 2). No patients had an SAE of irritability. Irritability led to discontinuation in 4 (0.4%) total PER (one 8mg; three 12mg) and 1 (0.2%) PBO. Aggression TEAEs occurred in a larger percentage of PER-treated adolescents [4 (7.8%)] than adults [13 (1.3%)] vs 0% and 2 (0.5%), respectively, for PBO. One of the 3 aggression SAEs occurred in a PER-treated adolescent.Conclusions: Patients should be monitored for aggression during PER treatment. The most common hostility/aggression-related TEAE using narrow and broad SMQ terms was irritability. Aggression TEAEs individually occurred at 1.6 % in PER vs 0.5% in PBO, with a dose-related increase; these events occurred with greater frequency in adolescents than adults.